Regioselective synthesis of 1,5-diaryl-1H-imidazoles by palladium-catalyzed direct arylation of 1-aryl-1H-imidazoles

Article abstract of DOI:10.1021/jo050274a

A variety of 1,5-diaryl-1H-imidazoles have been regioselectively synthesized by direct coupling of 1-aryl-1H-imidazoles with aryl iodides or bromides in DMF in the presence of CsF as the base and a catalyst precursor consisting of a mixture of Pd(OAc)

Full text of DOI:10.1021/jo050274a

Regioselective Synthesis of 1,5-Diaryl-1H-imidazoles by
Palladium-Catalyzed Direct Arylation of 1-Aryl-1H-imidazoles
Fabio Bellina,*,† Silvia Cauteruccio,† Luisa Mannina,‡ Renzo Rossi,*,† and Ste´phane Viel§
Dipartimento di Chimica e Chimica Industriale, University of Pisa, via Risorgimento 35, I-56126 Pisa,
Italy, Dipartimento S.T.A.A.M., University of Molise, I-86100 Campobasso, Italy, Istituto di Metodologie
Chimiche, CNR, via Salaria Km 29.300, I-00016 Monterotondo Stazione, Roma, Italy, and University of
Provence, Jeune Equipe Traces, Centre de Saint-Jerome, Case 511, 13397 Marseille Cedex, France
bellina@dcci.unipi.it; rossi@dcci.unipi.it
Received February 11, 2005
A variety of 1,5-diaryl-1H-imidazoles have been regioselectively synthesized by direct coupling of
1-aryl-1H-imidazoles with aryl iodides or bromides in DMF in the presence of CsF as the base and
a catalyst precursor consisting of a mixture of Pd(OAc)2 and AsPh3. The data obtained in this
synthetic study support a reaction mechanism involving an electrophilic attack of an arylpalladium-
(II) halide species onto the imidazole ring. Interestingly, some imidazole derivatives synthesized
in this study have been found to exhibit significant cytotoxic activity against human tumor cell
lines.
Introduction
focused on the use of 1-methyl-1H-imidazole,4a,5a 1-ben-
zyl-2-methyl-1H-imidazole,5a and 2-phenyl-1H-imidazole,5c
and no reports on the palladium-catalyzed direct aryla-
tion of 1-aryl-1H-imidazoles 1 have been described to
date.
In recent years, considerable attention has been di-
rected to the palladium-catalyzed direct intermolecular
C-arylation of π-excessive heteroaromatic compounds1
such as furans,2 thiophenes,2b,c,3 oxazoles,2a thiazoles,2a,4
imidazoles,2a,4a,5 indoles,5a,b,6 indolizines,7 and imidazo-
[1,2-a]pyrimidine.8 In fact, this method appears to have
a synthetically significant advantage, being able to lead
to carbon-carbon bond formation without involvement
of stoichiometric amounts of organometallic reagents.
However, the studies involving imidazoles have only been
It should also be noted that the results of the reaction
of 1-methyl-1H-imidazole with bromo- or iodobenzene in
(3) (a) Lavenot, L.; Gozzi, C.; Ilg, K.; Orlova, I.; Penalva, V.; Lemaire,
M. J. Organomet. Chem. 1998, 567, 49-55. (b) Gozzi, C.; Lavenot, L.;
Ilg, K.; Penalva, V.; Lemaire, M. Tetrahedron Lett. 1997, 38, 8867-
8870. (c) Se´vignon, M.; Papillon, J.; Schultz, E.; Lemaire, M. Tetrahe-
dron Lett. 1999, 40, 5873-5876. (d) Okazawa, T.; Satoh, T.; Miura,
M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286-5287. (e) Masui,
K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074-5075. (f)
Masui, K.; Mori, A.; Okano, K.; Takamura, K.; Kinoshita, M.; Ikeda,
T. Org. Lett. 2004, 6, 2011-2014.
(4) (a) Kondo, Y.; Komine, T.; Sakamoto, T. Org. Lett. 2000, 2, 3111-
3113. (b) Yokooji, A.; Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron 2003, 59, 5685-5689. (c) Mori, A.; Sekiguchi, A.; Masui,
K.; Shimada, T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J.
Am. Chem. Soc. 2003, 125, 1700-1701.
* To whom correspondence should be addressed. Phone:
+39.050.2219282. Fax: +39.050.2219260.
† University of Pisa.
‡ University of Molise and Istituto di Metodologie Chimiche, CNR.
§ Istituto di Metodologie Chimiche, CNR and University of Provence.
(1) For a review on the palladium-catalyzed arylation of heteroare-
nes and other aromatic compounds, see: Miura, M.; Nomura, M. Top.
Curr. Chem. 2002, 219, 211-241.
(5) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn. 1998, 71, 467-473. (b) Sezen, B.; Sames, D.
J. Am. Chem. Soc. 2003, 125, 5274-5275. (c) Sezen, B.; Sames, D. J.
Am. Chem. Soc. 2003, 125, 10580-10585.
(2) (a) Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga,
K.; Gohma, K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.;
Homma, R.; Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257-272. (b)
Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji,
A.; Nakata, T.; Tani, N.; Aoyagi, N. Heterocycles 1990, 31, 1951-1958.
(c) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M.
F. Org. Lett. 2003, 5, 301-304. (d) McClure, M. S.; Glover, B.; McSorley,
E.; Millar, A.; Osterhaut, M. H.; Roschangar, F. Org. Lett. 2001, 3,
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(6) Akita, Y.; Itagaki, Y.; Takizawa, S. Ohta, A. Chem. Pharm. Bull.
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10.1021/jo050274a CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/09/2005
J. Org. Chem. 2005, 70, 3997-4005
3997

Bellina et al.
SCHEME 1
Finally, our aim was also to exclude the involvement
of a Heck-type process in the palladium-catalyzed ary-
lation of compounds 1 by confirming that the mechanism
of this reaction is analogous to that proposed by Miura
for arylation of azole compounds5a and involves an
electrophilic attack to the most electron-rich position of
compounds 1 by the arylpalladium halide species formed
by oxidative addition of the aryl halide 2 to a palladium-
(0) species. In fact, conflicting mechanistic interpretations
of the palladium-catalyzed direct C-arylation of π-exces-
sive heteroarenes have been reported in the literature.
A Heck-type mechanism has been suggested for arylation
either of 3-carbalkoxyfurans and 3-carbalkoxythiophenes
in toluene in the presence of KOAc and a catalytic
amount of Pd(PPh3)42c or of thiophenes, which contain a
substituent such as CN, CHO, or NO2, in an acetonitrile/
water mixture in the presence of K2CO3, n-Bu4NBr, and
a catalytic amount of Pd(OAc)2.3a,b However, there is also
strong evidence that the palladium-catalyzed arylation
of π-excessive heteroarenes such as 2-furaldehyde,2d
imidazo[1,2-a]pyrimidine,8 thiazole, and 1-methyl-1H-
imidazole4a occurs at the site most susceptible to elec-
trophilic attack. Therefore, in these and other similar
cases3b,5b a mechanism involving an electrophilic aromatic
substitution has to be considered as the most probable.
DMF at 140 °C, in the presence of 2 equiv of K2CO3 or
Cs2CO3, respectively, and catalytic amounts of Pd(OAc)2
and PPh3,5a could lead us to believe that the palladium-
catalyzed direct arylation of 1-substituted 1H-imidazoles
has limited synthetic utility. In fact, this reaction fur-
nishes 5-phenyl-1-methyl-1H-imidazole together with
significant amounts of 2,5-diphenyl-1-methyl-1H-imida-
zole (Scheme 1).5a
Therefore, we set out to investigate the palladium-
catalyzed direct arylation of 1-aryl-1H-imidazoles 1 with
aryl halides 2, and to develop an effective procedure for
preparation of 1,5-diaryl-1H-imidazoles 3, we examined
the influence of factors such as the nature of the base to
be used in the reaction, the ligand of the catalyst system,
the type of halogen of the aryl halide 2, the presence in
1 and/or 2 of an electron-donor or an electron-withdraw-
ing group, the solvent, and the reaction temperature,
which might influence the selectivity and efficiency of the
reaction.
Our interest for the synthesis of compounds 3 was due
to the fact that the methods reported so far in the
literature for their preparation involve the construction
of their imidazole ring by multistep sequences,9 and yet
no simple and straightforward synthesis has been re-
ported. Moreover, 1,5-diaryl-1H-imidazoles include potent
and selective cyclooxygenase-2 inhibitors9e,10 and sub-
stances with antitubulin activity9d such as 4 and 5, which
represent cytotoxic Z-restricted analogues of combret-
astatin-A-4 (6).11 This last compound is a constituent of
the South African tree Combretum caffrum Kuntze
(Combretaceae)12 that inhibits both tubulin polymeriza-
tion and the binding of colchicine to tubulin13 and is also
able to elicit selective and potent toxicity toward tumors’
vasculature,14 leaving normal vasculature intact.14
Results and Discussion
Our study of the synthesis of 1,5-diaryl-1H-imidazoles
3 via palladium-catalyzed reaction of compounds 1 with
aryl halides was initiated by examining the reaction of
commercially available 1-phenyl-1H-imidazole (1a) with
4-methoxy(pseudo)halobenzenes 2a-c (Table 1), and at
first, we performed this reaction under experimental
(11) For the synthesis and evaluation of the cytotoxic activity of some
other Z-restricted five-membered heterocyclic analogues of combret-
astatin A-4, see: (a) Ohsuni, K.; Hatanaka, T.; Fujita, K.; Nakagawa,
R.; Fukuda, Y.; Nihei, Y.; Suga, Y.; Morinaga, Y.; Akiyama, Y.; Tsuji,
T. Bioorg. Med. Chem. Lett. 1998, 8, 3153-3158. (b) Nam, N.-H.; Kim,
Y.; You, Y.-J.; Hong, D.-H.; Kim, H.-M.; Ahn, B.-Z.; Bioorg. Med. Chem
Lett. 2001, 11, 3073-3076. (c) Kim, Y.; Nam, N.-H.; You, Y.-J.; Ahn,
B.-Z. Bioorg. Med. Chem. Lett. 2002, 12, 719-722. (d) Bellina, F.;
Anselmi, C.; Martina, F.; Rossi, R. Eur. J. Org. Chem. 2003, 2290-
2302. (e) Bellina, F.; Falchi, E.; Rossi, R. XVII National Meeting of the
Divisione di Chimica Farmaceutica of the Italian Chemical Society;
Sep 6-10, 2004, Pisa, Italy, Atti del Convegno P8. (f) Liou, J.-P.; Chang,
Y.-L.; Kuo, F.-M.; Chang, C.-W.; Tseng, H.-Y.; Wang, C.-C.; Yang, Y.-
N.; Chang, J.-Y.; Lee, S.-J.; Hsieh, H.-P. J. Med. Chem. 2004, 47, 4247-
4257. (g) Bellina, F.; Rossi, R. 26th Winter Meeting of the EORTC-
PAMM Group, Jan 26-29, 2005, Arcachon, France, Abstract P9.
(12) Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R.
K.; Schmidt, J. M.; Hogan, F. J. Med. Chem. 1995, 38, 1666-1672.
(13) Dark, G. G.; Hill, S. A.; Prise, V. E.; Tozer, G. M.; Pettit, G. R.;
Chaplin, D. J. Cancer Res. 1997, 57, 1829-1834.
(9) (a) Van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org.
Chem. 1977, 42, 1153-1159. (b) Kirchlechner, R.; Casutt, M.; Hey-
wang, U.; Schwarz, M. W. Synthesis 1994, 247-248. (c) Nunami, K.-
i.; Yamada, M.; Fukui, T.; Matsumoto, K. J. Org. Chem. 1994, 59,
7635-7642. (d) Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey,
R. W.; Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y.-H.; Marsh,
K.; Warner, R.; Lee, J. Y.; Zielinski-Mozng, Frost, D.; Rosenberg, S.
H.; Sham, H. L. J. Med. Chem. 2002, 45, 1697-1711. (e) Almansa, C.;
Alfo´n, J.; de Arriba, A. F.; Cavalcanti, F. L.; Escamilla, I.; Go´mez, L.
A.; Miralles, A.; Soliva, R.; Bartrol´ı, J.; Carceller, E.; Merlos, M.;
Rafanell, J. G. J. Med. Chem. 2003, 46, 3463-3475.
(10) Lui, H. X.; Zhang, R. S.; Yao, X. J.; Liu, M. C.; Hu, Z. D.; Fan,
B. T. J. Comput.-Aided Mol. Des. 2004, 18, 389-399.
(14) Lin, C.; Ho, H. H.; Pettit, G. R.; Hamel, W. Biochemistry 1989,
28, 6984-6991.
3998 J. Org. Chem., Vol. 70, No. 10, 2005

Regioselective Synthesis of 1,5-Diaryl-1H-imidazoles
TABLE 1. Screening Reaction Conditions for the Selective C-5 Arylation of 1a with (Pseudo)halides 2a-c
products
3a/7a/8a/9a
entrya
ligand
PPh3
PPh3
PPh3
P(o-Tolyl)3
P(t-Bu)3
aryl (pseudo)halide
base
conversion of 1ab
GLC molar ratio
yield of 3ab (%)
C-5 selectivityc
1
2d
3
2a
2a
2b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2a
2b
2a
2a
2a
2c
2c
2a
2a
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
CsF
CsF
CsF
CsF
K3PO4
CsF
CsF
CsF
CsF
63
60
52
76
99
43
26
99
89
75
78
75
65
84
89
81
47
63
87
73
57
50
27
64
72
61:11:8:20
70:15:0:15
53:18:7:22
50:10:14:26
36:48:8:8
55:17:3:25
46:37:0:17
54:8:22:16
75:8:4:13
63:13:3:21
52:12:16:20
63:2:3:32
84:9:0:7
39
35
19
50
31
22
12
50
39
37
33
62
49
61
40
61
27
32
43
48
26
34
9
0.76
0.82
0.68
0.68
0.39
0.73
0.55
0.64
0.86
0.80
0.65
0.93
0.90
0.89
0.95
0.86
0.77
0.63
0.93
0.88
0.84
0.87
0.92
0.79
0.72
4
5
6e
7f
8g
9
P(2-Furyl)3
AsPh3
AsPh3
AsPh3
AsPh3
AsPh3
PPh3
AsPh3
AsPh3
PPh3
P(4-CF3C6H4)3
dppb
dppf
dppf
dppb
10
11h
12
13i
14j
15
16
17
18
19
20
21
22
23
24
25
82:6:4:8
61:1:2:36
82:2:11:5
58:12:5:25
62:1:36:1
77:6:0:17
71:4:6:19
37:5:2:56
82:8:4:6
CsF
CsF
Cs2CO3
Cs2CO3
80:7:0:13
61:16:0:23
50:6:13:31
dppb
dppf
35
41
a Unless otherwise reported, the reactions were run with 1 mmol of 1a, 2 mmol of compounds 2a-c, 5 mol % of Pd(OAc)2, and 10 mol
% of monodentate ligand or 5 mol % of bidentate ligand in 5 mL of DMF at 140 °C for 48 h. b Determined by GLC analysis with use of
an internal standard (naphthalene). c The selectivity was expressed as the [3a/(3a + 7a + 8a)] molar ratio. d This reaction was performed
using a 1.3:1 molar ratio between 2a and 1a. e This reaction was performed using 5 mol % o Pd(PPh3)4. f In this reaction, 2.5 mol % of
trans-di(µ-acetato)bis[(di-o-tolylphosphino)benzyl]dipalladium(II) was used. g This reaction was carried out using 10 mol % of Pd(OAc)2.
h This reaction was run using a 4:1 molar ratio of AsPh3 and Pd(OAc)2. i This reaction was run in 5 mL of dioxane at 120 °C for 48 h.j This
reaction was run in 5 mL of toluene at 110 °C for 48 h.
conditions very similar to those used by Miura and co-
workers5a for C-arylation of 1-methyl-1H-imidazole. Thus,
1a was reacted with 2 equiv of iodide 2a and 2 equiv of
Cs2CO3 in DMF in the presence of 5 mol % Pd(OAc)2 and
10 mol % PPh3 at 140 °C for 48 h (Table 1, entry 1). After
this period of time, the conversion was found to be 63%
and the reaction mixture proved to contain the triary-
lated imidazole 8a, the expected monoarylation deriva-
tives 3a and 7a, PPh3, a significant amount of biphenyl
9a, and very small amounts of imidazoles 3b and 7b and
(4-methoxyphenyl)diphenylphosphine (10). It should be
noted that compounds 8a and 9a were formed concomi-
tantly with 3a and 7a.
Compound 9a presumably derived from a palladium-
catalyzed Ullmann-type reductive coupling of 2a15,16 and
(15) It should be noted that Miura and co-workers5a did not mention
the formation of a 2,5-diarylated compound in the palladium-catalyzed
reaction of 1-methyl-1H-imidazole with iodo- or bromobenzene. More-
over, these Authors did not report the presence in the reaction mixtures
of the homocoupling product derived from these halobenzenes.
(16) For examples of palladium-catalyzed Ullmann-type reductive
coupling of aryl halides, see: (a) Penalva, V.; Hassan, J.; Lavenot, L.;
Gozzi, C.; Lemaire, M. Tetrahedron Lett. 1998, 39, 2559-2560. (b)
Venkatraman, S.; Li, C.-J. Org. Lett. 1999, 1, 1133-1135.
J. Org. Chem, Vol. 70, No. 10, 2005 3999

Bellina et al.
compounds 3b and 7b very likely derived from the
reaction of 1a with palladium complex 12 which was
formed by an aryl-aryl exchange (eq 1)17 between the
palladium center and the PPh3 ligand of palladium
complex 11 obtained by oxidative addition of 2a to
catalytically active Pd(PPh3)2(OAc)-.18
3a was lower; thus, we thought it right to perform all of
the subsequent reactions using a 2:1 molar ratio between
compounds 2 and 1a. We also observed that the yield and
selectivity of the reaction carried out under the experi-
mental conditions of entry 1 were lowered either upon
changing the electrophile form iodide 2a to bromide 2b
(Table 1, entry 3) or using catalyst precursors such as
Pd(PPh3)4 (Table 1, entries 6). On the other hand, when
the PPh3 ligand of the palladium catalyst precursor was
replaced by P(o-Tolyl)3 (Table 1, entry 4), P(t-Bu)3 (Table
1, entry 5), P(2-furyl)3 (Table 1, entry 9), P(4-CF3C6H4)3
(Table 1, entry 19), or AsPh3 (Table 1, entries 10-14, 16,
and 17), cleaner reaction mixtures were obtained that
did not contain compounds derived from scrambling of
the aryl moiety of 2a with the organic group of the
ligands.
On the other hand, phosphine 10 also likely derived
from a palladium-catalyzed Pd-aryl/P-aryl exchange simi-
lar to that involved in the preparation of functionalized
arylphosphines by phosphination of aryl bromides using
triarylphosphines.19
Compound 3a was obtained in 39% GLC yield and with
a selectivity of 0.76 (Table 1, entry 1). Interestingly, pure
compounds 3a, 7a, and 8a could be isolated by chroma-
tography on silica gel of this complex reaction mixture,
and their structure could be unambiguously assigned on
We were then pleased to find that switching to CsF as
the base and using DMF as solvent and a catalyst
precursor consisting of a mixture of Pd(OAc)2 and AsPh3
in a 1:2 molar ratio (Table 1, entry 12) produced a
significant increase of the selectivity of the reaction which
in this case occurred in the homogeneous phase and
allowed us to obtain 3a in 62% yield. It should also be
noted that results comparable with those of this entry
could be obtained using dioxane or toluene as solvent
(Table 1, entries 13 and 14, respectively), even though
under these conditions the reaction occurred in the
heterogeneous phase. Moreover, high selectivity was also
observed when 2a was reacted with 1a in DMF in the
presence of CsF and the catalyst precursor consisting of
a mixture of Pd(OAc)2 and PPh3 (Table 1, entry 15) or a
mixture of Pd(OAc)2 and P(4-CF3C6H4)3 (Table 1, entry
19). However, in both these cases the yield was lower
than that obtained in entry 12 of Table 1 and the reaction
mixture obtained in entry 15 proved to be contaminated
by compounds derived from scrambling of the aryl moiety
of 2a with the phenyl group of PPh3.
1
the basis of their H and 13C NMR spectra at 600 and
150 MHz, respectively, and by a combination of 2D NMR
techniques that included 1H-13C heteronuclear single
1
quantum coherence (HSQC) and H-13C heteronuclear
multiple bond correlation (HMBC).
We then attempted to improve the conversion and
selectivity of this palladium-catalyzed reaction to mini-
mize the formation of byproducts and to successfully
develop a general catalytic protocol for preparation of 1,5-
diaryl-1H-imidazoles 3. Thus, the effects of a number of
variables such as the 2a/1a molar ratio, the nature of
the (pseudo)halogen substituent of compounds 2, the
base, the solvent, and the palladium derivative and its
ligand were carefully examined. As far as the conversion
is concerned, we found that running the reaction in the
presence of 10 mol % of Pd(OAc)2 under ligandless
conditions (Table 1, entry 8) gave quantitative results
after 48 h at 140 °C, but a large amount of 8a was formed
and 3a was obtained in low selectivity. An almost
quantitative conversion was also obtained using a mix-
ture of Pd(OAc)2 and P(t-Bu)3 as the catalyst (Table 1,
entry 5), but the yield of 3a and the C-5 selectivity of
the reaction proved to be very low. On the contrary, low
conversion (< 30%) was obtained in the reaction carried
out using Cs2CO3 as the base and a catalyst precursor
consisting of the Herrmann’s palladacycle20 (Table 1,
entry 7). In all of the other reactions performed using
Cs2CO3 as the base, ca. 50-90% conversions were ob-
tained after 48 h at 140 °C. We also found that when the
reaction was run using a 1.3:1 molar ratio between 2a
and 1a (Table 1, entry 2) its conversion was similar to
that of entry 1, but compound 3a was obtained in higher
selectivity and 8a was not formed. However, the yield of
Interestingly, satisfactory results could also be ob-
tained by reaction of 1a with bromide 2b using the
experimental conditions of entry 12 (Table 1, entry 16),
but low selectivity and/or yields were obtained by treat-
ment of 1a with 2a in the presence of the catalyst
precursors consisting of a mixture of Pd(OAc)2 and a
bidentate phosphine ligand such as dppb (Table 1, en-
tries 20, 23, and 24) or dppf (Table 1, entries 21 and
25). On the other hand, unsatisfactory results were
obtained in the reactions of 1a with triflate 2c in DMF
in the presence of CsF and catalytic amounts of Pd-
(OAc)2 and dppf (Table 1, entry 22) or dppb (Table 1,
entry 23).
Having successfully demonstrated the viability of
the Pd(OAc)2/AsPh3-catalyzed selective C-5 arylation of
1a with iodide 2a or bromide 2b in the presence of CsF
as the base, we then proceeded to test the scope
and limitations of this arylation reaction by applying
the optimized reaction conditions of entry 12 of Table
1 to the synthesis of 1,5-diaryl-1H-imidazoles 3 start-
ing from 1-aryl-1H-imidazoles 1a-g and commercially
available iodides 2a and 2d-j or aryl bromides 2b and
2k-m.
(17) (a) Kong, K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113,
6313-6315. (b) Goodson, F. E.; Wallow, T. I.; Novak, B. M. J. Am.
Chem. Soc. 1997, 119, 12441-12453. (c) Grushin, V. Organometallics
2000, 19, 1888-1900.
(18) (a) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576,
254-278. (b) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314-
321.
(19) Kwong, F. Y.; Lai, C. W.; Yu, M.; Chan, K. S. Tetrahedron 2004,
60, 5635-5645.
(20) Herrmann, W. A.; Beller, M.; Reisinger, C.-P.; O¨ fele, K.;
Brossmer, C.; Priermeier, T.; Fischer, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 1844-1848.
4000 J. Org. Chem., Vol. 70, No. 10, 2005

Regioselective Synthesis of 1,5-Diaryl-1H-imidazoles
SCHEME 2
SCHEME 3
Although several methods have been reported in the
literature for the synthesis of 1-aryl-1H-imidazoles 1,21
for preparation of compounds 1b-f we preferred the
method described in 1999 by Buchwald and co-workers21b
owing to its effectiveness and simplicity. Thus, an aryl
halide 2 was reacted with 1.5 equiv of imidazole (13) in
xylenes at 110 °C in the presence of 1.1 equiv of Cs2CO3,
5 mol % of trans,trans-dibenzylideneacetone (dba), 1
equiv of 1,10-phenanthroline, and 5 mol % of (CuOTf)2‚
toluene (Scheme 2).
high or complete selectivity. On the contrary, compound
3m was obtained in very low yield and selectivity since,
unexpectedly, its preparation from 1f and 2j (Table 2,
entry 17) furnished the C-2 arylation product, 7m, as the
main component of the reaction mixture.
Pure compounds 1b,d,e,f were so obtained in 96-99%
yield after chromatographic purification of the corre-
sponding crude reaction mixtures. However, the chro-
matographic separation of 1c from 1,10-phenanthroline
proved to be difficult. Thus, in this case, the crude
reaction mixture was first purified by chromatography
on silica gel and a CH2Cl2 solution of the product obtained
by concentration of the collected chromatographic frac-
tions was subsequently treated with a 1 M aqueous CuCl2
solution and then washed with water. Concentration of
the resultant CH2Cl2 solution allowed us to obtain pure
1c in 70% yield.
On the other hand, 1g was synthesized in 62% yield
by reaction of 13 with 1.03 equiv of NaH in DMF followed
by treatment with 1.03 equiv of fluoride 2n (Scheme 3).
Table 2 summarizes the results of the reactions per-
formed to prepare 1,5-diaryl-1H-imidazoles 3a-n. It
should be noted that these reactions, unlike those
reported in Table 1, were stopped when they did not
further progress. As illustrated in this table, the estab-
lished procedure provided a quick entry to compounds
3a-d,f,h-j,l,m and allowed us to obtain all these 1,5-
diaryl-1H-imidazoles, except 3m, in moderate yields and
The structural assignment of 1,5-diaryl-1H-imidazoles
1
3a-d,f,h-j,l,m was performed on the basis of their H
and 13C NMR spectra at 600 and 150 MHz, respectively,
and by a combination of 2D NMR techniques which
1
1
included H-13C HSQC and H-13C HMBC.
(21) (a) Johnson, A. I.; Kauer, J. C.; Sharma, D. C.; Dorfman, R. I.
J. Med. Chem. 1969, 12, 1024-1028. (b) Kiyomori, A.; Marcoux, J.-F.;
Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660. (c) Klapars,
A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 7727-7729. (d) Elliott, G. I.; Konopelski, J. P. Org. Lett. 2000, 2,
3055-3057. (e) Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J.
Org. Chem. 2001, 66, 1528-1531. (f) Antilla, J. C.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684-11688. (g) Liu,
J.; Chen, J.; Zhao, J.; Zhao, Y.; Li, L.; Zhang, H. Synthesis 2003, 2661-
2666. (h) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L.
J. Org. Chem. 2004, 69, 5578-5587. (i) Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607-5622. (j)
Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.; Xie, R. G. Chem. Commun.
2004, 188-189.
Moreover, the 13C NMR data of these imidazole deriva-
tives indicate that C-5 generally resonates at a higher
field than C-2 and that C-4 resonates at an intermediate
field with respect to C-2 and C-5. On the other hand, the
structures of 1,2-diaryl-1H-imidazoles 7a-d,f,h,m and
those of 1,2,5-triaryl-1H-imidazoles 8a-c,f,h,j, which
were obtained as coproducts of the palladium-catalyzed
reactions reported in Table 2, were preliminarily estab-
lished on the basis of their EI-MS spectra. However, the
structural assignments of compounds 7f and 8h were
J. Org. Chem, Vol. 70, No. 10, 2005 4001

Bellina et al.
TABLE 2. Palladium-Catalyzed Synthesis of 1,5-Diaryl-1H-imidazoles 3 from 1-Aryl-1H-imidazoles 1 and Aryl Halides 2
reagents
products
entry
1
Ar1
2
Ar2
X
reaction time (h) 3/7/8 GLC molar ratio
3
isolated yield (%)
1
2
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1b 4-MeOC6H4
1b 4-MeOC6H4
1b 4-MeOC6H4
2a 4-MeOC6H4
2b 4-MeOC6H4
2d Ph
I
Br
I
42
48
95:5:0
100:0:0
86:3:11
86:5:9
76:0:24
94:6:0
100: 0:0
88:3:9
52:11:37
3a
3a
3b
3c
3c
3d
3e
3f
49
43
41
38
59
39
a
36
22
b
40
61
55
72
b
3
23
4
2e
2l
2f
2i
4-CF3C6H4
4-CF3C6H4
4-ClC6H4
2-thienyl
I
Br
I
I
I
Br
I
I
17
5
66
6
67
7
67
8
2a 4-MeOC6H4
20
9
2b 4-MeOC6H4
2g 3,4,5-(MeO)3C6H2
91
3f
10
11
12
13
14
15
16
17
18
19
45
3g
3h
3h
3i
3j
3k
3l
3m
3n
3n
1c
1c
1c
1c
3,4,5-(MeO)3C6H2 2a 4-MeOC6H4
21
87:2:11
100:0:0
100:0:0
95:0:5
3,4,5-(MeO)3C6H2 2b 4-MeOC6H4
Br
I
46
3,4,5-(MeO)3C6H2 2h 1-naphthyl
3,4,5-(MeO)3C6H2 2k 3-F,4-MeOC6H3
68
Br
I
27
1d 1-naphthyl
1e 4-ClC6H4
2g 3,4,5-(MeO)3C6H2
2a 4-MeOC6H4
240
166
116
93
I
100: 0:0
17:43:40
36
9
b
b
1f
4-MeSC6H4
2j
4-FC6H4
I
1g 4-MeSO2C6H4
1g 4-MeSO2C6H4
2a 4-MeOC6H4
2b 4-MeOC6H4
I
Br
118
a The crude reaction mixture contained a very small amount of 3e. Thus, no attempt was made to isolate this compound. b Compound
1 was quantitatively recovered after the period of time reported in the table for this reaction.
SCHEME 4
SCHEME 5
confirmed by independent syntheses using procedures
very recently developed in our laboratory.22
Chromatographic purification allowed us to isolate 7f
in 34% yield. On the other hand, 8h was prepared in 21%
yield by treatment of 1c with 3 equiv of 2a in DMF at
140 °C for 114 h, in the presence of 10 mol % of Pd(OAc)2,
20 mol % of P(t-Bu)3, 3 equiv of CuI, and 3 equiv of CsF
(Scheme 5).
The data of Table 2 also show that, in addition to
several aryl iodides, aryl bromides 2b and 2k efficiently
participated in the selective palladium-catalyzed C-5
arylation of 1-aryl-1H-imidazoles such as 1a and 1c
(Table 2, entries 2 and 14). However, reaction of 2b with
1b furnished 3f in unexpectedly low yield and selectivity
(Table 2, entry 9). This reaction, similar to that reported
in entry 17 of Table 2, furnished a large amount of the
C-2 arylation product.
Remarkably, the palladium-catalyzed C-5 arylation of
compounds 1 proved to be highly sensitive to electronic
effects, and according to the mechanism proposed by
Miura and co-workers for arylation of azole compounds,5a
it was most efficient when compounds 1 having an
electron-rich aryl group linked to N-1 were used as
In particular, reaction of 1b with 2 equiv of 2a in DMF
at 140 °C for 20 h, in the presence of 10 mol % of Pd-
(OAc)2, 2 equiv of CuI, and 2 equiv of CsF, furnished a
reaction mixture which contained compounds 3f, 7f, and
8f in a 3:78:19 molar ratio, respectively (Scheme 4).
(22) The synthesis of 1,2-diaryl-1H-imidazoles and 1,2,5-triaryl-1H-
imidazoles by palladium- and copper-mediated reaction of 1-aryl-1H-
imidazoles with aryl halides will be described in detail in a forthcoming
paper.
4002 J. Org. Chem., Vol. 70, No. 10, 2005

Regioselective Synthesis of 1,5-Diaryl-1H-imidazoles
substrates. On the other hand, no reaction occurred when
imidazole 1 was characterized by a strong electron-
withdrawing group such as 4-MeSO2C6H4 (Table 2,
entries 18 and 19). It should also be noted that activated,
unactivated and moderately deactivated aryl halides such
as 2e, 2d, and 2a, respectively, were tolerated as elec-
trophilic partners of the arylation reaction, but strongly
deactivated iodide 2g proved to be unable to participate
to the reaction (Table 2, entries 10 and 15). This was also
hampered by the presence of a sulfur-containing aryl
group in 1 (Table 2, entries 17-19) or a sulfur-containing
electrophile such as 2i (Table 2, entry 7).
Finally, it is worth mentioning that some compounds
synthesized in this study were tested in vitro for cyto-
toxicity against the NCI three-cell line panel consisting
of MCF7, SF-268, and NCI-H460, and compounds which
reduced the growth of any one of these cell lines to 32%
or less were considered active and passed on for evalu-
ation over a 5-log dose range in the NCI’s in vitro human
disease-oriented tumor cell line screening panel that
consisted of 60 human tumor cell lines. 1,5-Diaryl-1H-
imidazoles 3c, 3f, and 3h, 1,2-diaryl-1H-imidazole 7f, and
1-aryl-1H-imidazole 1c were found to be significantly
cytotoxic, but among the compounds tested, 3h, which
represents a Z-restricted analogue of combretastatin A-4
Experimental Section
General Procedure for the Synthesis of 1-Aryl-1H-
imidazoles 1b-f. To a flame-dried reaction vessel were added
imidazole (13) (2.04 g, 30.0 mmol), 1,10-phenanthroline (3.60
g, 20.0 mmol), trans,trans-dibenzylidene acetone (dba) (0.23
g, 1.0 mmol), Cs2CO3 (7.17 g, 22.0 mmol), copper(I) triflu-
omethanesulfonate toluene complex (0.52 g, 1.0 mmol), and
an aryl iodide 2 (20.0 mmol), if a solid. The reaction vessel
was fitted with a silicon septum, evacuated, and back-filled
with argon, and this sequence was repeated twice. Xylenes (4
mL) and an aryl iodide 2 (20.0 mmol), if a liquid, were then
added successively under a stream of argon by syringe at room
temperature. The resulting mixture was stirred under argon
at 110 °C until GLC analysis showed that the reaction was
complete (24-91 h). The resultant heterogeneous mixture was
allowed to cool to room temperature, diluted with EtOAc,
filtered through a plug of silica gel, and eluted with additional
EtOAc. The filtrate was concentrated under reduced pressure,
and the residue was purified by MPLC on silica gel to provide
the desired product. This procedure allowed us to prepare
compounds 1b,d-f in 96-99% yield. However, the chromato-
graphic separation of 1c from 1,10-phenanthroline proved to
be difficult. Thus, the chromatographic fractions that cor-
responded to the purification of 1c using a 96:4 mixture of CH2-
Cl2 and methanol as eluent were collected, concentrated, and
then dissolved in CH2Cl2. The resultant solution was thor-
oughly washed with a 1 M aqueous CuCl2 solution and water,
dried, filtered over Celite, and concentrated under reduced
pressure. Chemically pure 1c was so obtained in 70% yield.
Characterization of compounds 1b-f can be found in the
Supporting Information.
(6), proved to be the most potent (MG-MID log GI50
-7.09).
)
1-[4-(Methylsulfonyl)phenyl]-1H-imidazole (1g). A 60%
suspension of NaH in mineral oil (0.80 g, 20.0 mmol) was
washed with pentane (5 mL), and the resultant solid was
suspended in DMF (20 mL) and treated under argon with a
solution of imidazole (13) (1.33 g, 19.5 mmol) in DMF (10 mL).
The mixture was stirred for 20 min at room temperature, and
then a solution of 1-fluoro-4-(methylsulfonyl)benzene (2n) (3.48
g, 19.2 mmol) in DMF (5 mL) was added during 4 min. The
resultant mixture was stirred for 19 h at room temperature
and then poured into an ice-cooled saturated NH4Cl solution
and extracted with EtOAc. The organic extract was washed
with water, dried, and concentrated under reduced pressure,
and the residue was purified by MPLC on silica gel with a
96:4 mixture of CH2Cl2 and methanol as eluent to give 1g (2.56
g, 62%) as a colorless solid: mp 180-181 °C; 1H NMR (200
MHz, CDCl3) δ 8.11 (s, 1H, H-2), 8.03 (m, 2H, H-3′ and H.5′),
7.63 (m, 2H, H-2′ and H-6′), 7.40 (br s, 1H, H-5), 7.27 (br s,
1H, H-4), 3.12 (s, 3H, Me); 13C NMR (50.3 MHz, CDCl3) δ 141.2,
139.0, 135.3, 131.4, 129.5 (2C), 121.3 (2C), 117.6, 44.5; IR (KBr)
νmax 1596, 1510, 1421, 1145, 953, 840, 779 cm-1; EI-MS: m/z
223 (13), 222 (100), 207 (21), 159 (15), 143 (32), 132 (13), 116
(43), 89 (17), 63 (8). Anal. Calcd for C10H10N2O2S: C, 54.04;
H, 4.53. Found: C, 53.98; H, 4.58.
General Procedure for the Palladium-Catalyzed Syn-
thesis of 1,5-Diaryl-1H-imidazoles 3 from Compounds 1
and Aryl Halides 2. To a flame-dried reaction vessel were
added compound 1 (1.0 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol),
CsF (0.30 g, 2.0 mmol), AsPh3 (30.6 mg, 0.1 mmol), and an
aryl iodide or bromide 2 (2.0 mmol), if a solid. The reaction
vessel was fitted with a silicon septum, evacuated, and back-
filled with argon, and this sequence was repeated twice. DMF
(5 mL) and an aryl iodide or bromide 2 (2.0 mmol), if a liquid,
were then added successively under a stream of argon by
syringe at room temperature. The resulting mixture was
stirred at 140 °C under argon for the period of time reported
in Table 2. The completion of the reaction and the composition
of the reaction mixture were established on the basis of GLC
and GLC-MS analyses of a sample of the crude reaction
mixture treated with a saturated aqueous NaCl solution and
extracted with AcOEt. After being cooled to room temperature,
the reaction mixture was diluted with AcOEt, poured into a
Conclusion
In conclusion, this work has demonstrated that a
variety of 1,5-diaryl-1H-imidazoles can be selectively
synthesized in moderate yields by direct palladium-
catalyzed C-arylation of 1-aryl-1H-imidazoles with aryl
iodides or bromides. This preparation method, which is
quite simple and practical, favorably competes with those
previously described in the literature which are based
on the construction of the imidazole ring,9 even though
it suffers from a limitation due to the fact that this Pd-
catalyzed arylation is hampered by the presence of a
sulfur atom in the imidazole substrate or the electrophile.
Data have also been obtained in support of the reaction
mechanism proposed by Miura5a for arylation of azoles,
which involves an electrophilic attack of an arylpalladium
halide species onto position C-5 of the heteroaromatic
ring. This position has been reported to be more reactive
then C-4 and C-2 in electrophilic substitution reactions.5a
The arylpalladium(II) species can be generated from an
activated, unactivated, or moderately deactivated aryl
bromide or iodide. Moreover, strongly deactivated 3,4,5-
trimethoxyphenyl iodide has been proven to be unable
to participate to the arylation reaction of 1-aryl-1H-
imidazoles, and compound 1g, which possesses a strong
electron-withdrawing group at its N-1, did not undergo
the Pd-catalyzed reaction.
It is also worth mentioning that some imidazole
derivatives synthesized in this study have been found to
be cytotoxic against human cancer cell lines and that one
among these substances exhibited potent activity.
Further studies on the highly selective synthesis of
potentially cytotoxic imidazole derivatives by direct C-
arylation reactions are underway.
J. Org. Chem, Vol. 70, No. 10, 2005 4003

Bellina et al.
saturated aqueous NaCl solution, and extracted with AcOEt.
The organic extract was washed with water, dried, and
concentrated under reduced pressure. The residue was purified
by MPLC on silica gel. 1,5-Diaryl-1H-imidazoles 3a, 3h, and
3i are representative of those prepared using this procedure.
5-(4-Methoxyphenyl)-1-phenyl-1H-imidazole (3a). The
crude reaction product, which was obtained in entry 1 of Table
2 by palladium-catalyzed reaction of 1a with 2a, was purified
by MPLC on silica gel with a mixture of toluene and EtOAc
(50:50 + 0.1% Et3N) as eluent to give 3a (0.12 g, 49%) as a
white solid: mp 121-123 °C; 1H NMR (600 MHz, CDCl3) δ
7.77 (br s, 1H, H-2), 7.40 (m, 2H, H-3′′ and H-5′′), 7.38 (m,
1H, H-4′′), 7.22 (br s, 1H, H-4), 7.19 (m, 2H, H-2′′ and H-6′′),
7.06 (m, 2H, H-2′ and H-6′), 6.79 (m, 2H, H-3′ and H-5′), 3.78
(s, 3H, OMe); 13C NMR (150 MHz, CDCl3) δ 159.3 (C-4′), 138.0
(C-2), 136.5 (C-1′′), 132.9 (C-5), 129.6 (C-3′′ and C-5′′), 129.5
(C-2′ and C-6′), 128.3 (C-4′′), 127.1 (C-4), 125.6 (C-2′′ and C-6′′),
121.4 (C-1′), 114.0 (C-3′ and C-5′), 55.2 (OMe); IR (KBr) νmax
2982, 1614, 1515, 1255, 1181, 1027, 807 cm-1; EI-MS m/z 251
(17), 250 (100), 235 (44), 208 (15), 207 (26), 180 (10), 77 (14),
40 (12). Anal. Calcd for C16H14N2O: C, 77.78; H, 5.64. Found:
C, 77.61; H, 5.57.
(C-2′′ and C-6”), 60.9 (OMeb), 56.0 (OMea); IR (KBr) νmax 2937,
1601, 1508, 1242, 1125, 1102, 77 cm-1; EI-MS m/z 361 (25),
360 (100), 345 (26), 317 (4), 287 (4), 166 (7), 151 (6). Anal. Calcd
for C22H20N2O3: C, 73.32; H, 5.59. Found: C, 73.19; H, 5.63.
The characterization of all the other 1,5-diaryl-1H-imida-
zoles prepared in this study can be found in the Supporting
Information.
1,2-Bis(4-methoxyphenyl)-1H-imidazole (7f). Compound
7f, which was obtained as a byproduct in the reactions
corresponding to entries 8 and 9 of Table 2, was synthesized
according to the following procedure. To a flame-dried reaction
vessel were added 1b (0.17 g, 1.0 mmol), 2a (0.47 g, 2.0 mmol),
Pd(OAc)2 (22.4 mg, 0.1 mmol), CuI (0.38 g, 2.0 mmol), and CsF
(0.30 g, 2.0 mmol). The reaction vessel was fitted with a silicon
septum, evacuated, and back-filled with argon, and this
sequence was repeated twice. DMF (5 mL) was then added
under a stream of argon by syringe at room temperature, and
the resulting mixture was stirred under argon at 140 °C for
20 h. After this period of time, GLC and GLC-MS analyses
of a sample of the reaction mixture, which was treated with a
saturated aqueous NH4Cl solution and extracted with AcOEt,
showed that the reaction was complete and the reaction
mixture contained compounds 3f, 7f, and 8f in a ca. 3:78:19
molar ratio, respectively. Thus, it was cooled to room temper-
ature, diluted with AcOEt, and poured into a saturated
aqueous NH4Cl solution, and the resulting mixture was stirred
in the open air for 0.5 h. It was then extracted with AcOEt,
and the organic extract was washed with brine, dried, and
concentrated under reduced pressure. The residue was purified
by MPLC on silica gel with a mixture of CH2Cl2 and methanol
(98:2) as eluent to give 7f (95 mg, 34%) as a white solid: mp
107-109 °C; 1H NMR (600 MHz, CDCl3) δ 7.39 (d, J ) 8.3
Hz, 2H, H-2′ and H-6′), 7.28 (br s, 1H, H-4), 7.16 (m, 2H, H-2′′
and H-6′′), 7.10 (br s, 1H, H-5), 6.93 (m, 2H, H-3′′ and H-5′′),
6.81 (d, J ) 8.3 Hz, 2H, H-3′ and H-5′), 3.85 (s, 3H, OMeb),
3.79 (s, 3H, OMea); 13C NMR (150 MHz, CDCl3) δ 160.4 (C-4′),
159.7 (C-4′′), 146.3 (C-2), 131.0 (C-1′′), 130.2 (C-2′ and C-6′),
127.2 (C-2′′ and C-6′′), 126.0 (C-4), 122.8 (C-5), 121.0 (C-1′),
114.8 (C-3′′ and C-5′′), 113.9 (C-3′ and C-5′), 55.6 (OMeb), 55.3
(OMea); IR (KBr) νmax 2962, 1608, 1515, 1502, 1250, 1022, 831
cm-1; EI-MS m/z 281 (19), 280 (100), 279 (33), 265 (21), 238
(16), 147 (17). Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75.
Found: C, 72.67; H, 5.66.
5-(4-Methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-
imidazole (3h). The crude reaction product, which was
obtained in entry 12 of Table 2 by palladium-catalyzed reaction
of 1c with 2b, was purified by MPLC on silica gel with a
mixture of CH2Cl2 and methanol (97:3) as eluent to give 3h
(0.21 g, 61%) as an orange low-melting solid. 1H NMR (600
MHz, CDCl3) δ 7.79 (br s, 1H, H-2), 7.21 (br s, 1H, H-4), 7.09
(d, J ) 8.7 Hz, 2H, H-2′ and H-6′), 6.82 (d, J ) 8.7 Hz, 2H,
H-3′ and H-5′), 6.38 (s, 2H, H-2′′ and H-6′′), 3.86 (s, 3H, OMec),
3.79 (s, 3H, OMea), 3.71 (s, 3H, OMeb); 13C NMR (150 MHz,
CDCl3) δ 159.3 (C-4′), 153.6 (C-3′′ and C-5′′), 137.9 (C-2 and
C-4′′), 133.1 (C-5), 132.0 (C-1′′), 129.6 (C-2′ and C-6′), 126.8
(C-4), 121.5 (C-1′), 114.0 (C-3′ and C-5′), 103.3 (C-2′′ and C-6′′),
61.0 (OMec), 56.3 (OMeb), 55.3 (OMea); IR (KBr) νmax 2940,
1596, 1504, 1244, 1177, 1027, 807 cm-1; EI-MS m/z 341 (22),
340 (100), 325 (17), 298 (9), 282 (10), 267 (5), 255 (4), 207 (5),
154 (5). Anal. Calcd for C19H20N2O4: C, 67.04; H, 5.92:
Found: C, 66.94; H, 5.81.
1-(3,4,5-Trimethoxyphenyl)-5-(1-naphthyl)-1H-imida-
zole (3i). The crude reaction product, which was obtained in
entry 13 of Table 2 by palladium-catalyzed reaction of 1c with
2h, was purified by MPLC on silica gel with a mixture of
EtOAc and toluene (90:10 + 0.1% Et3N) as eluent to give 3i
(0.20 g, 55%) as a pale yellow solid: mp 132-133 °C; 1H NMR
(600 MHz, CDCl3) δ 8.15 (br s, 1H, H-2), 7.87 (d, J ) 8.1 Hz,
1H, H-8′), 7.86 (d, J ) 8.0 Hz, 1H, H-5′), 7.76 (d, J ) 8.3 Hz,
1H, H-4′), 7.48 (m, 1H, H-6′), 7.43 (m, 2H, H-7′ and H-3′), 7.38
(br s, 1H, H-4), 7.34 (dd, J ) 7.1 and 1.2 Hz, 1H, H-2′), 6.27
(s, 2H, H-2′′ and H-6′′), 3.73 (s, 3H, OMeb), 3.47 (s, 3H, OMea);
13C NMR (150 MHz, CDCl3) δ 153.3 (C-4′′), 137.6 (C-3′′ and
C-5′′), 137.1 (C-2), 133.4 (C-9′), 132.8 (C-10′), 131.5 (C-1′′), 131.1
(C-5), 129.5 (C-8′ and C-2′), 128.4 (C-5′), 128.3 (C-4), 126.9 (C-
3′), 126.4 (C-1′), 126.3 (C-6′), 125.3 (C-4′), 125.1 (C-7′), 102 0.2
1-(3,4,5-Trimethoxyphenyl)-2,5-bis(4-methoxyphenyl)-
1H-imidazole (8h). To a flame-dried reaction vessel were
added 1c (0.23 g, 1.0 mmol), 2a (0.70 g, 3.0 mmol), Pd(OAc)2
(22.4 mg, 0.1 mmol), CuI (0.57 g, 3.0 mmol), and CsF (0.46 g,
3.0 mmol). The reaction vessel was fitted with a silicon septum,
evacuated, and back-filled with argon, and this sequence was
repeated twice. DMF (5 mL) and P(t-Bu)3 (50 µL, 0.2 mmol)
were then added successively under a stream of argon by
syringe at room temperature. The resulting mixture was
heated to 140 °C under argon with stirring and maintained
at this temperature for 114 h. GLC and GLC-MS analyses of
4004 J. Org. Chem., Vol. 70, No. 10, 2005

Regioselective Synthesis of 1,5-Diaryl-1H-imidazoles
a sample of the reaction mixture, which was treated with a
saturated aqueous NH4Cl solution and extracted with AcOEt,
showed the presence of two new compounds in a ca. 1:1 molar
ratio and of unreacted 1c and 2a. However, the conversion of
the reaction did not significantly increase after further stirring
for 12 h at 140 °C. Thus, the reaction mixture was cooled to
room temperature, diluted with AcOEt, and poured into a
saturated aqueous NH4Cl solution. The resulting mixture was
stirred in the open air for 0.5 h and extracted with AcOEt.
The organic extract was washed with brine, dried, and
concentrated under reduced pressure, and the residue was
purified by MPLC on silica gel with a mixture of CH2Cl2 and
methanol (98:2) as eluent to give 6h (94 mg, 21%) as a white
solid: mp 129-131 °C; 1H NMR (600 MHz, CDCl3) δ 7.38 (m,
2H, H-2′′ and H-6′′), 7.29 (br s, 1H, H-4), 7.04 (m, 2H, H-2′
and H-6′), 6.81 (m, 2H, H-3′′ and H-5′′), 6.80 (m, 2H, H-3′ and
H-5′), 6.29 (m, 2H, H-2′′ and H-6′′), 3.88 (s, 3H, OMec), 3.79
(s, 3H, OMea), 3.78 (s, 3H, OMed), 3.60 (s, 3H, OMeb); 13C NMR
(150 MHz, CDCl3) δ 160.1 (C-4′′). 159.3 (C-4′), 153.6 (C-3′′ and
C-5′′), 146.9 (C-2), 138.3 (C-4′′), 134.6 (C-5), 132.1 (C-1′′), 130.1
(C-2′′ and C-6′′), 129.8 (C-2′ and C-6′), 125.2 (C-4), 121.6 (C-1′
and C-1′′), 113.9 (C-3′′ and C-5′′), 113.8 (C-3′ and C-5′), 105.9
(C-2′′ and C-6′′), 61.2 (OMec), 56.3 (OMeb), 55.3 (OMed and
OMea); IR (Kbr) νmax 2940, 1595, 1499, 1246, 1128, 1029, 840
cm-1; EI-MS m/z 447 (28), 446 (100), 431 (11), 298 (4), 271 (5),
223 (4), 133 (4). Anal. Calcd for C26H26N2O5: C, 69.94; H, 5.87.
Found: C, 69.77; H, 5.75.
Acknowledgment. We thank the Ministero
dell’Istruzione, dell’Universita` e della Ricerca (MIUR),
and the University of Pisa for financial support. We are
also grateful to Mr. Piergiorgio Vergamini for recording
IR spectra.
Supporting Information Available: Experimental pro-
cedures, characterization for compounds 1b-f and 3b-
1
d,f,j,l,m and H and 13C data for compounds 7a and 8a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO050274A
J. Org. Chem, Vol. 70, No. 10, 2005 4005